We have investigated virologic and immunologic events associated with acute HIV infection. High levels of HIV DNA and RNA synthesis in peripheral blood mononuclear cells and high levels of plasma viremia were detected in the setting of acute HIV infection. Dramatic decreases in HIV RNA in peripheral blood mononuclear cells and in plasma viremia coincided with the emergence of HIV-specific immune responses; however, the frequency of HIV-infected cells (i.e., latently infected cells harboring HIV DNA but not expressing HIV RNA) remained high. Serial lymph node biopsies were obtained from monkeys after infection with simian immunodeficiency virus (SIV) in order to examine early events in lymphoid tissue. Individual cells productively infected with SIV were detected in lymph nodes as early as 7 days after infection. Over the next several weeks, the number of productively infected cells decreased in lymphoid tissue, coincident with a decrease in plasma viremia and generation of SIV-specific immune responses. Trapping of virions in the follicular dendritic cell network of lymph node germinal centers predominated following a rise in SIV-specific complement-binding antibody titers. Similar kinetics of HIV distribution in lymph nodes were observed in a cross sectional study of individuals from whom lymph node biopsies were obtained at various times after primary HIV infection. Despite the fact that a dramatic decrease in the number of HIV-expressing cells in lymph nodes occurs in concert with the decrease in plasma viremia approximately 4 weeks after acute infection, it is clear that the number of HIV-expressing cells in lymph nodes is still high in patients with recent (up to 20 months) acute infection compared with patients in the early chronic phase of disease (i.e., approximately 3 years after acute infection): these results are important with regard to the development of guidelines for the duration of antiviral treatment following acute HIV infection. The early immune response to acute HIV infection is characterized by major expansions in CD8+ T cells from different T cell receptor (TCR) Vbeta families. These cells mediated specific anti-HIV cytotoxic activity. Nucleotide sequences of recombinant clones of the expanded Vbeta families demonstrated the oligoclonal (i.e., antigen-specific) nature of these expansions. HIV-infected individuals who exhibited expansion of a single Vbeta family during primary infection experienced rapid depletion of CD4+ T cells and maintained high levels of plasma viremia 1 year after acute infection, whereas individuals who had minimal or no expansions in multiple Vbeta families experienced slower loss of CD4+ T cells and harbored lower viral loads at 1 year post-infection. These results suggest that enhanced plasticity of the host immune response against HIV is associated with more efficient control of viral replication and improved prognosis. Expanded CTL clonotypes were found preferentially in peripheral blood compared with lymph nodes following acute HIV infection. Deletion of these expanded clonotypes in the absence of viral mutations corresponding to the clonotypes suggests that failure of the immune response to eliminate HIV may be due to exhaustion of the capacity of the immune system by overwhelming levels of viral replication. Analysis of cytokine mRNA expression from serial blood samples obtained at different times after acute infection revealed that a peak of interferon-gamma (IFN-gamma) expression coincided with the peak of CD8+ T-cell expansion. Furthermore, increased plasma levels of the beta-chemokines RANTES, MIP-1alpha, and MIP-1beta were detected in the weeks following acute HIV infection, although no relationship to other immunologic or virologic parameters could be discerned.